The present invention relates generally to imaging systems. More specifically the present invention relates to novel micro-CT scanners that incorporate internal gain charge-coupled devices (CCD). Further, a combined positron emission tomography (PET)/CT imaging system is also provided.
Dedicated high-resolution small animal imaging systems have recently emerged as important new tools for cancer research. These systems permit noninvasive screening of animals for mutations or pathologies and to monitor disease progression and response to therapy. Among these, x-ray microcomputed tomography (microCT), shows promise as a cost-effective means for detecting and characterizing soft tissue structures, skeletal abnormalities, and tumors in live animals (Paulus et al., IEEE Trans. Nucl. Sci. 46:558-564 (1999); Paulus et al., Neoplasia 2:62-70 (2000)). Current CT systems provide high-resolution images with excellent sensitivity to skeletal tissue and good sensitivity to soft tissue, particularly when contrast-enhancing media are employed. However, use of this powerful modality for functional studies such as those of tumor vascular physiology or involving true whole organ physiologic imaging is difficult due to the lack of a suitable x-ray imaging detector. Typically, such studies require a detector that can simultaneously provide high speed, high sensitivity, and a large active imaging area.
In 1987 Flannery et al. (Flannery et al., Science 237:1439-1444 (1997); Flannery et al., J. Appl. Phys. 62:4668-4674 (1987)) brought x-ray microtomography into a new era with the introduction of a three-dimensional imaging system using a two-dimensional detector comprising of a phosphor plate optically coupled to a charge-coupled device (CCD) array. This, coupled with the development of a new three-dimensional “cone-beam” image reconstruction algorithm (Feldkamp et al., J. Opt. Soc. Am. 1:612-619 (1984)), spurred the development of a large number of microtomography systems for high-resolution specimen analysis in the 1990s. The majority of the studies performed using these instruments focused on high-density tissue such as bone or teeth for which magnetic resonance imaging is less successful. For in vivo small animal studies, particularly large population studies, these systems become cumbersome to operate because the subject must be confined in a rotating carrier designed to prevent soft-tissue organ motion. Recently, dedicated small animal microCT scanners have been developed in which the detector and x-ray source rotate about a fixed “patient bed” much like clinical CT systems. A table of the currently available micro-CT systems from various manufacturers is included below.
TABLE ISome of the major small animal micro-CT systems and the manufacturers currently in market.ReconstructionMainManufacturerModelX-ray SourceX-ray DetectorMax. object sizeResolutionapplicationSKYSCAN1072μ-focus, 5 μm1024 × 102420 mm @Electronic(high-(4W)/8 μm12-bit cooled CCD,1K × 1K,components,resolution/(8W), 0-100 kV,3.7:1 fiberoptic37 mm @biomedicalCone-0-250 μAtaper coupled to2K × 2Kobjects,beamscintillator(2) 20-50 mm @compositesscanner)(2) 768 × 5121K × 1Ketc.8 bit CCD, lenscoupled toscintillator107420-40 kV/768 × 576 8-bit,16-30 mm40 μm or 22 μmMetal foams,(portable/0-1000 μAlens-coupled toplastics,Cone-scintillatorcomposites,beambiomedicalscanner)objects1076μ-focus, 20-4000 × 2300 12-68 or 35 mm Φ,1000 × 1000 toIn-vivo small(high-100 kV, 10W,bit cooled with200 mm long8000 × 8000,animalresolution/5 μm (4W)fiberoptic9 μm/18 μm/35 μmimagingCone-coupled tobeamscintillatorscanner)10782 tubes, 20-65 kV1280 × 102448 mm Φ,512 × 512 × 512 @High-(high-each, 40 W each12-bit140 mm long94 μm orthroughputspeed/1024 × 1024 × 1024in-vitro/in-Cone-@ 47 μmvivo smallbeamanimalscanner)imagingSCANCOμ-CT 20μ-focus 5-7 μm,Max. FOV = 17.4512 × 512 orBiomedicalMedical(high-50 kVp/32mm, 50 mm long1024 × 1024, slice:objectsresolution/keV(160 μA)25-35 μmFan-beam)μ-CT 40μ-focus 5-7 μm,2048 × 256,FOV = 12-37512 × 512 orBiomedical(high-30-70 kVp/20-5024 μm pitchmm, 80 mm long1024 × 1024 orobjects,resolution/keV(160 μA)2048 × 2048,small animalCone-6-72 μm isotropicimagingbeam)μ-CT 80μ-focus 5-7 μm,2048 × 128,FOV = 76 mm,512 × 512 orBiomedical(high-30-70 kVp/20-5048 μm pitch120 mm long1024 × 1024 orobjects,resolution/keV(160 μA)2048 × 2048,small animallarge10-74 μm nominalimagingsamples/isotropicCone-beam)Viva-CTμ-focus 5-7 μm,2048 × 252,FOV = 20-38512 × 512 orBiomedical4030-70 kVp/20-5026 μm pitchmm, 145 mm1024 × 1024 orobjects,(high-keV(160 μA)long2048 × 2048,small animalspeed)10-72 μm nominalimagingisotropicGE MedicalMS μ-CTμ-focus, 20-70 mm × 70 mmMax. Φ = 40 mm10-100 μmBiomedicalSystems(cone-90 kVp, 0.18 mAarea, 2048 × 2048objects,beam)(max.)pixel CCDtissuespecimensRS μ-CT80 kVp, W3500 × 175090 mm Φ ×90/45 μm,In vivo, in(cone-targetCCD, 10 μm45 mm long1750 × 1750 × 875vitro,beam)pixelsVolumetricsmall animalCTImTek Inc.MicroCA80 kVp, 9 μm,Up toImaging area upImage circle fromIn vivo,T IIW target4096 × 4096to 110 mm ×35 mm to 110 mmVolumetricCCD, cooled,110 mmΦsmall animalfiberoptic taperCTcoupled toscintillator
While the above systems are capable of mass production of small animal CT systems, at present they do not incorporate high speed CT technology. In particular, most of the conventional systems employ CCD based detector arrays, micro-focus x-ray tubes, and have reconstructed image resolution between 50 and 100 microns. It is important to note that some of the existing microCT systems are not capable of in vivo imaging, while others having this capacity are limited by their speed of operation resulting in data acquisition times of several minutes to hours. Thus, the existing systems cannot be used for high-speed dynamic, i.e., functional, studies, where high sensitivity and high-speed x-ray imaging is required. For example, the fastest scan time among the conventional current high-throughput systems is provided by SkyScan-1078, which is about 49 seconds at 94 μm resolution and 1.44 degree rotational steps (250 views).
Most of the current microCT systems employ CCD based detector arrays which provide adequate spatial resolution (50 to 100 μm) and imaging area (5 cm×5 cm), but offer limited imaging speeds of 1 to 5 seconds per projection. This translates into volumetric data acquisition times in the range of 5 to 30 minutes for high resolution imaging, making it impossible to use them for functional studies. As microCT devices are not yet capable of functional imaging, important functional and physiologic studies in animal models of various diseases such as solid tumors, stroke physiology, and acute myocardial ischemia, are performed using existing clinical CT scanners. The clinical CT scanners can provide the required temporal resolution, but offer a tradeoff between spatial resolution and imaging volume. For example, the GE LightSpeed multi-slice CT scanner can provide 2 cm image coverage with a 0.5 cm (500 μm) slice thickness or a 0.5 cm image coverage with a 0.125 cm (125 μm) slice thickness, and a 300×300 μm nominal, in plane resolution. Even though the existing clinical scanners are capable of cine-mode data acquisition, only from a limited volume. For example, a 2 cm-long volume can be studied if a slice thickness of 5 mm is used. Also, the minimum slice thickness is limited to 1.25 mm, and in this mode only 5 mm of the volume is covered.
Additional difficulties arise from the fact that the image voxels are anisotropic, which lead to severe partial volume artifacts in small animal imaging, where each voxel represents a heterogeneous sample of various tissue components and the calculated physiologic parameters represent an average physiological behavior at best. Thus, the limited spatial resolution and small volume coverage associated with the current CT scanners are suboptimal for small animal functional studies related to accurate characterization of tissue-specific physiology. Isotropic dynamic perfusion studies and whole organ physiologic imaging, require detectors with 100 to 300 frames per second readout, spatial resolution of ˜100 μm, and a x-ray detection efficiency of >85%. Such an imaging system allows a repeated volumetric data acquisitions in seconds.
The limitations of current CCD based microCT x-ray imaging systems arise from two factors. First, readout speeds are curtailed in order to minimize the system read noise, which increases with the readout rates. An increased read noise reduces the signal to noise ratio (SNR) and the effective dynamic range of the detector. Recently developed CCD based x-ray imaging systems address the speed issue to some extent, however, at the cost of reduced SNR, pixel resolution, and sensitivity. Second, the CCDs themselves are not used for x-ray detection. Rather, a high density scintillator is placed between the x-ray beam and the CCD, so that the x-rays are stopped in the scintillator, their energy converted to light photons, which are subsequently detected by the CCD. In most systems that typically use Gd2O2S (GOS) phosphors, such as the Kodak® MinR-2000, the sensitivity is limited due to the tradeoff between x-ray stopping power and spatial resolution. Thicker GOS screens improve sensitivity, but reduce the spatial resolution because the light photons spread from the conversion point, and scatter as well. Thus, there is a need for improved speed, spatial resolution and SNR. At present important functional, physiologic studies of various diseases such as solid tumors, stroke physiology, and acute myocardial ischemia in small animal models are performed using clinical CT scanners. This is due to the fact that microCT devices are not yet capable of the high processing speeds and resolution necessary for functional imaging.
The development of high-speed microCT systems allows for the use of CT for functional imaging, substantially enhancing the role of this powerful technique, which is already well established for anatomical imaging. Functional micro-CT provides a novel approach for longitudinal high-resolution investigations of, for example, new anti-angiogenic therapies by using perfusion imaging of a tumor. Moreover, investigations of stroke physiology and developing new therapeutic approaches for treatment of acute cerebral ischemia will largely benefit from the availability of a high resolution imaging modality with enough active imaging area to cover the whole organ of interest. This approach will substantially improve the accuracy of the quantification of physiologic parameters, such as blood flow (BF), blood volume (BV), transcapillary transfer constants (K1, k2), extraction fraction (E) and permeability surface area product (PS).
In addition to the tissue specific physiology studies, functional CT techniques are also being used for experimental studies of solid tumor vascular physiology and angiogenesis, and its inhibition by anti-angiogenic therapies in mice. Additionally, studies of cerebrovascular physiology in experimental stroke models in rats, rabbits, and monkeys, and investigations of myocardial ischemia are in progress. In all such functional CT studies a short bolus of radio-opaque contrast agent is administered and its first passage, which takes only a few seconds, is recorded through the region of interest. Several images have to be acquired at closely spaced time intervals in order to apply tracer kinetic modeling to these temporal data for quantification of physiologic parameters.
Transgenic and “knock-out” mice have provided important insights into the genetic mechanisms underlying atherosclerosis, hypertension, and diabetes. However, similar advances in the field of myocardial infarction (MI) have been impeded by the challenge of performing coronary ligation during survival surgery in animals weighing 30 g or less. Nevertheless, this challenge has been overcome in recent years and numerous studies now demonstrate the feasibility of inducing MI in intact mice. Thus the surgical challenge has now given way to the technical challenge of assessing myocardial infarction, left ventricular dimensions, and cardiac function in very small animals with high heart rates (>500 bpm). Although it is possible to non-invasively assess myocardial perfusion and infarction in patients with radionuclide techniques, the limited spatial and temporal resolution of, for example, Single Photon Emission Computed Tomography (SPECT), effectively precludes its application in mice. However, more accurate measurements can be made through the use of cardiac magnetic resonance imaging (MRI), which has emerged as one of the most powerful modalities currently available for the noninvasive assessment of ischemic heart disease.
Although the utility of MRI for imaging cardiac structure, function, and infarct size in mice has been well established, there are several disadvantages with MRI that limit its widespread application in biomedical research. First, a high cost associated with high field strength (e.g., ≧4.7 T) MRI imaging limits its accessibility to researchers. Second, the high field strength magnets preclude the use of any metallic objects in or on the animal or as part of support equipment. Third, the overall time for setup and imaging small animals with MRI can be quite lengthy. Finally, due to the high heart rates in small animal models, particularly mice (>500 BPM), cardiac MRI does not provide the required temporal resolution to capture the first-pass of a contrast agent in order to obtain the input function that would allow the assessment of myocardial perfusion in the mouse. A high temporal resolution CT system is expected to allow simultaneous assessment of myocardial perfusion and function in the mouse heart. The ability to correlate flow and function is of great importance in cardiovascular research which cannot be performed using MRI. In addition to cardiac functional analysis, there are novel applications, such as liposomal CT contrast agents, for assessing myocardial perfusion and risk area in the murine heart. The advantage of the liposomal contrast agent over the standard contrast agents that are usually employed with CT or MR imaging is that the liposomal agent remains trapped intravascularly allowing accurate assessment of myocardial perfusion and risk area.
Over the recent years, researchers have been combining data from various modalities such as, for example, positron emission tomography (PET) and MRI to provide complementary data for diagnosis. Similarly, there is a significant interest in combining image data from microPET and microCT, and combining the modalities of SPECT and CT.